Safety Assessment of Hydroxyethyl Urea as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Hydroxyethyl Urea, which is reported to function as a humectant and a hair and skin conditioning agent. The Panel reviewed the available data to determine the safety of this ingredient. The Panel concluded that Hydroxyethyl Urea is safe in cosmetics in the present practices of use and concentration described in the safety assessment when formulated to be non-irritating.

64Cu production via the 68Zn(p,nα)64Cu nuclear reaction: An untapped, cost-effective and high energy production route.

INTRODUCTION: Copper-64 (64Cu, t1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy. METHODS: 64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 µA using 200 mg 68Zn encapsulated within an aluminum­indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T. RESULTS: Maximum purified activity of 4.9 GBq [64Cu]CuCl2 was obtained in 5 mL of pH 2-3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/µmol, 155 ± 31 GBq/µmol, 266 ± 34 GBq/µmol, and 117 ± 2 GBq/µmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUVmean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUVmean of 0.76 ± 0.14 after 60 min post-injection. CONCLUSIONS: 64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy.

Role of Pimavanserin Treatment-Continuity on Discharge From Long-term Care: Assessing the Quality of Antipsychotic Medication Review.

Objective: To investigate the role of (1) antipsychotic medication review (AP-MR) documentation quality of Minimum Data Set 3.0 (MDS) surveys, and (2) treatment-continuity on discharge-to-community and clinical outcomes among long-term care (LTC) residents treated with pimavanserin. Design, Setting, and Participants: A retrospective cohort analysis of Parts A, B, and D claims from Medicare 100% sample merged with MDS data from June 2016 through December 2018 was conducted. Residents with more than 100-day LTC stay and 1 pimavanserin prescription or more with completed antipsychotic-use MDS question were selected. AP-MR documentation quality (ie, gradual dose reduction [GDR] attempts, clinical contraindication to GDR), discharge-to-community, and clinical outcomes (eg, falls, fractures) were obtained from MDS. Treatment-continuity was assessed from Part D claims. Data Analysis: Descriptive statistics (frequencies, proportions, Chi-square tests, and means) and adjusted logistic regressions (ORs with 95% CIs reported association between pimavanserin treatment-continuity and discharge-to-community. Results: Of 4,021 eligible residents, 29% (n = 1,182) attempted a GDR per AP-MR MDS documentation. Approximately 41% (n = 1,665) had documentation showing GDR was clinically contraindicated, yet 39% (n = 645) still attempted GDR. While overall discharge-to-community rates were low, it was significantly higher (P < 0.05) among LTC residents continuing (14.94%; n = 380/2,546) versus discontinuing (11.84%; n = 171/1,444) pimavanserin. OR for treatment-continuity was 1.96, 95% CI 1.50-2.55. Residents continuing pimavanserin had lower incidents of falls (2.8% vs 9.4%), hip fractures (0.29% vs 0.69%), and pelvic/femur fractures (0% vs 0.92%) versus those residents who discontinued it. Conclusions: Among LTC-stay residents, high discordance between GDR rates and AP-MR MDS documentation quality was observed. Pimvanserin treatment-continuity showed greater likelihood of discharge-to-community; continued documentation training can ensure appropriate antipsychotic use with a balanced benefit:risk profile.

Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer.

BACKGROUND: Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. METHODS: A quantitative high-throughput drug screening of 4,991 compounds was performed on two ACC cell lines, SW13 and NCI-H295R, based on antiproliferative effect and caspase-3/7 activity. The top candidate drugs were pairwise combined to identify the most potent combinations. The synergistic efficacy of the selected inhibitors was tested on tumorigenic phenotypes, such as cell proliferation, migration, invasion, spheroid formation, and clonogenicity, with appropriate mechanistic validation by cell cycle and apoptotic assays and protein expression of the involved molecules. We tested the efficacy of the drug combination in mice with luciferase-tagged human ACC xenografts. To study the mRNA expression of target molecules in ACC and their clinical correlations, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas. RESULTS: We chose the maternal embryonic leucine zipper kinase (MELK) inhibitor (OTS167) and cyclin-dependent kinase (CDK) inhibitor (RGB-286638) because of their potent synergy from the pairwise drug combination matrices derived from the top 30 single drugs. Multiple publicly available databases demonstrated overexpression of MELK, CDK1/2, and partnering cyclins mRNA in ACC, which were independently associated with mortality and other adverse clinical features. The drug combination demonstrated a synergistic antiproliferative effect on ACC cells. Compared to the single-agent treatment groups, the combination treatment increased G2/M arrest, caspase-dependent apoptosis, reduced cyclins A2, B1, B2, and E2 expression, and decreased cell migration and invasion with reduced vimentin. Moreover, the combination effectively decreased Foxhead Box M1, Axin2, glycogen synthase kinase 3-beta, and ß-catenin. A reduction in p-stathmin from the combination treatment destabilized microtubule assembly by tubulin depolymerization. The drug combination treatment in mice with human ACC xenografts resulted in a significantly lower tumor burden than those treated with single-agents and vehicle control groups. CONCLUSIONS: Our preclinical study revealed a novel synergistic combination of OTS167 and RGB-286638 in ACC that effectively targets multiple molecules associated with ACC aggressiveness. A phase Ib/II clinical trial in patients with advanced ACC is therefore warranted.

Mortality Among Parkinson's Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries.

OBJECTIVE: Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database. METHODS: This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW). RESULTS: Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients. CONCLUSIONS: Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.

Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial.

Importance: Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. Objective: To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. Design, Setting, and Participants: The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. Interventions: Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. Main Outcomes and Measures: The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. Results: Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. Conclusions and Relevance: In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. Trial Registration: ClinicalTrials.gov Identifier: NCT02929329.

Risk of Hospitalization and Death Associated With Pimavanserin Use in Older Adults With Parkinson Disease.

BACKGROUND AND OBJECTIVES: To determine the risk of hospitalization and death associated with pimavanserin use. METHODS: We conducted a retrospective cohort study of adults 65 years and older with Parkinson disease between November 1, 2015, and December 31, 2018, using an administrative dataset on residents of Medicare-certified long-term care facilities and linked Medicare claims data. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance pimavanserin users and nonusers on 24 baseline characteristics. Fine-Gray competing risk and Cox proportional hazards regression models were used to estimate the risk of hospitalization and death up to 1 year, respectively. RESULTS: The study cohort included 2,186 pimavanserin users and 18,212 nonusers. There was a higher risk of 30-day hospitalization with pimavanserin use vs nonuse (IPTW-adjusted hazard ratio [aHR] 1.24, 95% confidence intervals [CI] 1.06-1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR 1.10, CI 0.99-1.24) or with 30-day mortality (aHR 0.76, CI 0.56-1.03). Pimavanserin use vs nonuse was associated with increased 90-day mortality (aHR 1.20, CI 1.02-1.41) that persisted after 180 days (aHR 1.28, CI 1.13-1.45) and 1 year (aHR 1.56, CI 1.42-1.72). DISCUSSION: Pimavanserin use vs nonuse in older adults was associated with an increased risk of hospitalization at 1 month of initiation and a higher risk of death for up to 1 year following initiation. These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk/benefit balance among patients with Parkinson disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with Parkinson disease who are 65 or older and residing in Medicare-certified long-term care facilities, pimavanserin is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.

Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis.

BACKGROUND: Pimavanserin is approved for treatment of Parkinson disease (PD)-related psychosis, but its use has been associated with an increased risk of death during clinical trials, as well as during postmarketing surveillance. Previous reports on the association between pimavanserin and mortality have not taken into account limitations of data sources nor included comparable populations or comparisons to relevant treatment alternatives. OBJECTIVE: To conduct a comparative pharmacovigilance assessment of pimavanserin vs treatment alternatives and by restricting surveillance data to more representative populations. METHODS: This was a retrospective analysis of adverse event case reports submitted to the FDA's Adverse Event Reporting System (FAERS) from 2016 through 2019 quarter 3 (Q3). FAERS data are collected from the full population, were further restricted to only those with PD, and were based on PD medication use. Reports were assessed for exposure to pimavanserin, clozapine, quetiapine, haloperidol, and other atypical antipsychotics. The outcome of interest was all-cause death. A proportional reporting ratio (PRR) and 95% confidence limits were calculated for each 2 by 2 contingency of outcome (death) and exposure (pimavanserin and others). For each outcome/exposure pair, the baseline population was altered to include the full FAERS sample, only reports with PD, reports with PD treated with levodopa, and reports with PD treated with multiple PD medications. The sample was also stratified by time period before April 2018 and after September 2018 to capture periods of public knowledge and federal response. A lower 95% CI (Lower95CI) ≥ 2 for the PRR was considered as the accepted threshold for a drug safety signal. RESULTS: As of 2019 Q3, there were 2,287 reports of death associated with pimavanserin. Compared within the full FAERS base population, pimavanserin yielded a PRR Lower95CI = 2.08 but was smaller when restricted to comparison among only a base population with PD (Lower95CI = 1.09), PD treated with levodopa (Lower95CI = 1.15), or PD treated with multiple PD medications (Lower95CI = 1.63). Metrics for quetiapine, clozapine, and other atypical antipsychotics were similar in magnitude. Stratification by time showed a possible reporting bias associated with pimavanserin, since no safety signal was detected before April 2018; however, a signal was present thereafter. CONCLUSIONS: Compared in context with treatment alternatives for patients with PD, pimavanserin was not associated with excess reports of death in the FAERS data. This information should be used in shared decision making between physicians and PD patients to balance the risks and benefits of pimavanserin and other treatments for PD psychosis. DISCLOSURES: No outside funding supported this study. The authors report no disclosures or conflicts of interest relevant to this study. Armstrong receives research support from the NIA (P30AG047266, R01AG068128) and the Florida Department of Health (grant 20A08). She is the local principal investigator of a Lewy Body Dementia Association Research Center of Excellence. She also receives compensation from the American Academy of Neurology for work as an evidence-based medicine methodology consultant. She is on the level of evidence editorial board for Neurology and related publications (uncompensated), receives publishing royalties for Parkinson's Disease: Improving Patient Care (Oxford University Press, 2014), and has received an honorarium for presenting for Medscape CME in 2018. Okun serves as a consultant for the Parkinson's Foundation and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. Okun has participated as a site principal investigator and/or co-investigator for several NIH-, foundation-, and industry-sponsored trials over the years but has not received honoraria. Malaty has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, Abbvie, Boston Scientific, Eli Lilly, Neuroderm, Pfizer, Revance, and Teva. She has received travel compensation and/or honoraria from the Tourette Association of America, NeuroChallenge Foundation and NIH/Neurobiology of Disease in Children, Parkinson Foundation, Medscape, International Association of Parkinsonism and Related Disorders, and Cleveland Clinic, and royalties from Robert Rose publishers. The other authors have no disclosures.

Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.

The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1-h period (short access [ShA]), 6-h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, increased motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and stronger cue-induced reinstatement compared with rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin neurons. Together, these results indicate that the IntA model is a useful tool in the study of opioid addiction and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.

Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System.

BACKGROUND: The prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared with male rats. METHODS: Here, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (α) of 3 types of palatable food (low fat, high fat, and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we also examined the role of orexin function in sex differences of economic demand for palatable foods. RESULTS: The novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, we observed more orexin-expressing neurons and Fos expression (measure of recent neural activation) in these neurons in female rats compared with male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low- and high-cost intake for palatable food in both male and female rats. CONCLUSIONS: These findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.

Association of Pharmaceutical Industry Payments to Physicians With Prescription and Medicare Expenditures for Pimavanserin.

OBJECTIVE: This study aimed to quantify the association between pharmaceutical industry payments to physicians for pimavanserin and both pimavanserin prescription volume and Medicare expenditures. METHODS: This retrospective cross-sectional study used 2016 and 2017 data from Open Payments and the Medicare Part D Prescriber Public Use Files. The authors used Poisson regression models to quantify the association between physician payments for pimavanserin and pimavanserin prescription volume and linear regression models to quantify the association with Medicare expenditures for pimavanserin. RESULTS: Of 1,609 physicians who prescribed pimavanserin, 45% received payments, which totaled to $6,369,922. Each $10,000 in physician payments was associated with a 14% increase in pimavanserin prescription volume (incident rate ratio=1.14, 95% confidence interval [CI]=1.13-1.14). Every $100 in physician payments was associated with a $175.84 increase in Medicare pimavanserin expenditures (95% CI=$161.55-$190.13). CONCLUSIONS: Extensive physician payments have been associated with increased pimavanserin prescription volume and Medicare expenditures.

Blinded SAPS-PD Assessment After 10 Weeks of Pimavanserin Treatment for Parkinson's Disease Psychosis.

BACKGROUND: Parkinson's disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP. OBJECTIVE: Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study. METHODS: Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales. RESULTS: Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was - 3.4 (6.3); p < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (-6.9 vs. -6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE. CONCLUSION: Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks.

The arousal effect of hyperbaric oxygen through orexin/hypocretin an upregulation on ketamine/ethanol-induced unconsciousness in male rats.

Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.

Cost-Effectiveness Analysis of Landiolol, an Ultrashort-Acting Beta-Blocker, for Prevention of Postoperative Atrial Fibrillation for the Germany Health Care System.

OBJECTIVES: Landiolol is an ultrashort-acting beta-blocker with high beta-1 receptor affinity and less blood pressure-lowering properties than other beta-blockers available for intravenous use in Germany. The present analysis aimed to determine whether perioperative treatment with landiolol in cardiac surgical patients is cost-effective under the conditions of the German Diagnosis-Related Groups health cost reimbursement system. DESIGN: On the basis of clinical outcome data from a meta-analysis that included 622 patients from 7 randomized controlled trials, a decision-model was developed to determine the cost-effectiveness of landiolol versus standard-of-care (SoC). SETTING: Hospital setting. PARTICIPANTS: Hospital patients undergoing a representative mix of cardiac surgical procedures (MIX-CS) and isolated coronary artery bypass grafting (CABG). INTERVENTIONS: Landiolol versus SoC in prevention of atrial fibrillation immediately after cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The model benefit was expressed in a reduction of postoperative atrial fibrillation (POAF) episodes and reduced complications. The model calculated total inpatient costs over the hospital length of stay. Costs from published sources were used for the German hospital perspective. SoC was associated with POAF rates of 36.0% to 39.2% and 24.4% to 30.1% in the MIX-CS and CABG populations, respectively. Patients with POAF had a higher morbidity and mortality. Estimated total costs for SoC patients in the MIX-CS and CABG groups were 28.792 € and 25.630 €, respectively. Landiolol reduced the incidence of POAF to 12.6% in the MIX-CS and 12.1% in the CABG groups. This was associated with a cost reduction of 2.209 € and 1.470 €. CONCLUSIONS: This analysis suggests that preventing POAF with landiolol is highly cost-effective. Additional studies are needed to assess whether a comparable reduction in POAF and associated cost savings may be achieved using conventional intravenous beta-blockers or amiodarone.

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil.

Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; α) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline α values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists.SIGNIFICANCE STATEMENT Abuse of opioids has risen rapidly and continues to be a major health crisis. Thus, there is an urgent need to better understand the neurobiological and behavioral mechanisms underlying opioid addiction. Here, we investigate the role of orexin-1 receptor signaling (OxR1) within ventral pallidum (VP) in remifentanil demand and cue-induced reinstatement of remifentanil seeking. Using a within-session behavioral economics procedure, we show that intra-VP microinjections of the OxR1 antagonist SB-334867 decreased motivation (increased demand elasticity) without affecting remifentanil consumption at low effort. We also found that SB microinjected intra-VP attenuated cue-induced reinstatement of remifentanil seeking. Together, our results support a role for VP OxR1 signaling in opioid reward.

The role of orexin-1 receptor signaling in demand for the opioid fentanyl.

The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with high abuse liability. Here, we established a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigated the utility of our procedure to predict OxR1 antagonism efficacy and relapse propensity. Demand parameters α (demand elasticity or price sensitivity of consumption, an inverse measure of drug motivation) and Qo (drug consumption at null cost) were assessed. The OxR1 antagonist SB-334867 (SB) decreased motivation (increased α) for fentanyl without affecting Qo. Baseline α values predicted SB efficacy, such that SB was most effective at reducing motivation (increasing α) in highly motivated rats. Baseline α values predicted the amount of cued reinstatement of fentanyl seeking; this reinstatement behavior was attenuated by SB administration. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.

Development and design of novel cardiovascular therapeutics based on Rho kinase inhibition-In silico approach.

Rho kinases, one of the best-known members of the serine/threonine (Ser/Thr) protein kinase family, can be used as target enzymes for the treatment of many diseases such as cancer or multiple sclerosis, and especially for the treatment of cardiovascular diseases. This study presents QSAR modeling for a series of 41 chemical compounds as Rho kinase inhibitors based on the Monte Carlo method. QSAR models were developed for three random splits into the training and test set. Molecular descriptors used for QSAR modeling were based on the SMILES notation and local invariants of the molecular graph. The statistical quality of the developed model, including robustness and predictability, was tested with different statistical approaches and satisfying results were obtained. The best calculated QSAR model had the following statistical parameters: r2 = 0.8825 and q2 = 0.8626 for the training set and r2 = 0.9377 and q2 = 0.9124 for the test set. Novel statistical metric entitled as the index of ideality of correlation was used for the final model assessment, and the obtained results were 0.6631 for the training and 0.9683 for the test set. Molecular fragments responsible for the increases and decreases of the studied activity were defined and they were further used for the computer-aided design of new compounds as potential Rho kinase inhibitors. The final assessment of the developed QSAR model and designed inhibitors was achieved with the application of molecular docking. An excellent correlation between the results from QSAR and molecular docking studies was obtained.

Orexin 1 receptors in the anterior cingulate and orbitofrontal cortex regulate cost and benefit decision-making.

Orexin neurons are discretely localized within the lateral hypothalamus and have widespread projections into all areas of the brain. In addition, several lines of evidence specify that orexins may also participate in the regulation of a variety of affective and cognitive processes. The Orexin-1 receptor (OX1r) is distributed extensively throughout the prefrontal cortex (PFC). Delay-based decision- making is mediated largely by the orbitofrontal cortex (OFC) while effort- based decision-making is controlled by the anterior cingulated cortex (ACC). Hence, in the present study, a series of experiments were conducted to clarify the role of OX1r in the mPFC (ACC and/or OFC) in cost and benefit decision-making. The rats were trained in a delay and/or effort-based form of cost-benefit T-maze decision-making task. Two goal arms were different in the amount of accessible reward and cost. Before surgery, all animals were selecting the high reward arm and pay the cost on almost every trial. During the test days, the rats received local injections of either DMSO 20% /0.5 µl, as a vehicle, or SB334867 (3, 30 and 300 nM/0.5 µl), as a selective OX1r antagonist, within the ACC and/or OFC. The results of this study showed that the bilateral microinjection of SB334867 into ACC and/or OFC changed the preference to a low reward arm with no cost, indicating the role of OX1 receptors in cost and benefit decision- making. From these results, it can be implied that OX1 receptors in the mPFC play a crucial role for allowing the animal to evaluate and pay the cost to acquire greater rewards.